PT108082B - MACROMOLECULAR COMPLEXES OF TRANSITION METALS FOR CANCER TREATMENT AND ITS PREPARATION PROCESS - Google Patents

Abstract

THE PRESENT INVENTION REFERS TO MACROMOLECULAR COMPLEXES OF TRANSITION METALS, TO THEIR PREPARATION PROCESSES, AND TO BIDENTED AND MONODENTATED MACROLIGANDOS. THE INVENTION ALSO REFERS TO PHARMACEUTICAL COMPOSITIONS AND MEDICINES CONTAINING THE REFERRED MACROMOLECULAR COMPLEXITIES OF TRANSITION METALS AND THE USE OF THE FIRST PHARMACEUTICAL COMPOSITIONS, MEDICINES AND MACROMOLECULAR COMPLEXITIES OF TRANSITION METALS IN ANTICHRICATING AND / OR PREVENTION IN THERAPY AND / OR PREVENTION IN AND THERAPY AND / OR PREVENTION. SOLIDS, LIQUIDS AND / OR METASTASES AND / OR AS A RADIOSENSITIZING AGENT.

Description

DESCRIPTION

MACROMOLECULAR COMPLEXES OF TRANSITION METALS FOR CANCER TREATMENT AND ITS PREPARATION PROCESS

Field of the Invention

The present invention relates to macromolecular complexes of transition metals, to pharmaceutical compositions containing them, to their use in medicine, in particular as antitumor and antimetastatic agents, as well as to the process of preparing them.

State of the art

Metal complexes are now recognized as an emerging class of potentially very effective agents for treating cancer.

A. Valente, MH Garcia, F. Marques, Y. Miao, C. Rousseau, P. Zinck, First polymer 'ruthenium-cyclopentadienyl' complex as potential anticancer agent, Journal of Inorganic Biochemistry 2013, 127, 79-81 describe a class of ruthenium compounds synthesized using methyl 2,3,4-tri-Obenzyl-aD-glucopyranoside (a molecule of biological interest) as the initiator of lactide polymerization catalyzed by dimethylaminopyridine, resulting in a polylactide functionalized at the end of the chain with a Substituted D-glucose; later, this polymer reacted with 2,2'-bipyridine-4,4'-dicarbonyl dichloride giving rise to the macroligand containing an ester attached to each of the bipyridine rings, with about 75% purity. The final compound results from the synthesis between this macroligand and ο [Ηη (η ⁵ C5H5) (PPh3) 2Cl] in the presence of silver triflate in dichloromethane.

1/59 WO 2007 / 128158A1 application (DYSON, Paul, Joseph et al) discloses transition metal complexes to inhibit resistance in the treatment of cancer and metastasis. This application covers several families of transition metal complexes; however, it does not disclose complexes with macroligands in its constitution.

EP 07101258.7 discloses organometallic compounds for the treatment of cancer; however, there is no indication of compounds containing macromolecular ligands.

In the review article Polymer-Metal Complexes (PMC) for Cancer Therapy (A. Valente, P. Zinck, Recent Research Developments in Polymer Science, 11 (2012): 99-128, published by Transworld Research Network, Trivandrum, India (ISBN : 97881-7895-538-4)), the main families of compounds containing polymers in their constitution are mentioned. Most of them have been reported using platinum as the central metal and without using the cyclopentadienyl ligand. The vast majority of approaches are multinuclear, that is, each compound molecule has several metallic centers in its constitution.

The review article for macromolecular ruthenium compounds Syntheses of macromolecular ruthenium compounds: a new approach to the search for anticancer drugs (A. Valente, MH Garcia, Inorganics 2014, 2, 96-114) makes reference to approaches to cancer therapy using macromolecular ruthenium compounds. All approaches found in the literature are multinuclear approaches and the only disclosure that contemplates the cyclopentadienyl ligand is the article referred to above (A. Valente, MH Garcia, F. Marques, Y. Miao, C. Rousseau, P. Zinck, First polymer ' rutheniumcyclopentadienyl 'complex as potential anticancer agent, Journal of Inorganic Biochemistry 2013, 127, 79-81). Advantageously, the complexes of the present invention are

2/59 mononuclear (i.e. they contain only one metal atom per molecule), which allows precise control of the amount of drug to be administered.

Developing effective methods by which drugs are administered and delivered to their target is as important in combating cancer as the efficiency of the drug itself.

In addition, there is a need for compounds that are therapeutically more effective and yet are able to overcome the side effects of chemotherapy caused by the currently available drugs.

Several treatment approaches with multinuclear macromolecular metallic compounds present the problem of administration in an approximate percentage of metal for a certain amount of drug, therefore feeling a great need for greater rigor and control over the amount of metal in administration.

Another felt need is the stability of the new compounds in an aqueous medium.

The present invention provides new metal complexes and new drugs and pharmaceutical compositions that contain them that can be distributed to cancer cells with high efficiency and precision, due to the inclusion of macroligands and / or molecules of biological interest in the sphere of coordination of the metals used.

The new complexes of the present invention include a polymeric ligand and, consequently, have high molecular weight. This feature allows the benefit of increased permeation and retention in tumor tissues, which results in a preferential accumulation in these tissues compared to what can occur in healthy tissues (enhanced permeation and retention effect, EPR effect (J. Kopecek, P. Kopeckova, T. Minko, ZR Lu, HPMA copolymer-anticancer drug conjugates:

3/59 design, activity, and mechanism of action, 2000, Eur. J. Pharm. Biopharm; Y. Matsumura, H. Maeda, A New Concept for Macromolecular Therapeutics in Cancer Chemotherapy: Mechanism of Tumoritropic Accumulation of Proteins and the Antitumor Agent Smancs, 1986, Cancer Res.) This is possible since tumors, with very rapid cell growth and abnormal, have poor vascularization, allowing molecules with high molecular mass to enter cells, but have difficulty getting out, causing a greater accumulation in tumor tissue over time. In this way, a drastic reduction in side effects can be achieved in relation to molecules with a low molecular weight, which can freely enter and exit tumor tissues (S. Parveen, R. Misra, SK Sahoo, Nanoparticles: a boon to drug delivery, therapeutics , diagnostics and imaging, 2012, Nanomedicine: Nanotechnology, Biology and Medicine).

The present invention also provides new processes for the synthesis of macromolecular complexes of transition metals, including macromolecules and metallopharmaceuticals. In addition, the synthesis processes of the present invention provide molecules of the compounds of the present invention with a precise, controlled amount of metal, with a degree of purity comprised between 80-95% and consequently such compounds are suitable for controlled administration.

The results already gathered indicate that both the macromolecular compounds of the present invention when administered or their fragments originating under the specific conditions found in the tumor maintain the desired cytotoxic activity.

The compounds of the present invention are stable in air and in an aqueous medium for periods of time suitable for use as medicaments and have improved cytotoxicity over the drug in clinical use, cisplatin. These

4/59 are important and advantageous characteristics when it is intended to develop new drugs.

The new class of compounds object of the present invention has application in the treatment of cancer, both of the main tumor and of the metastases originated therefrom.

Since the compounds of the present invention absorb visible light, they can also generate reactive oxygen species in the excited state (singlet), and be used in photodynamic therapy for the treatment of superficial cancers such as skin cancer, pharynx, among others.

The present invention relates to pharmaceutical compositions. The complexes and compositions according to the invention can be used, for example, as medicaments in the treatment of tumors, both of the main tumor and of the metastases, originating therefrom, including in photodynamic therapy for the treatment of superficial cancers such as skin and pharynx , among others.

Such complexes and compositions are intended for use via topical, intravenous, subcutaneous and intraperitoneal administration.

These and other advantages of the present invention will become more evident and will be better understood using the figures, description and attached claims that follow.

Objectives, advantages and additional features will become evident to those skilled in the art by analyzing the description or practicing the invention.

In addition, the present invention encompasses all possible combinations of the particular and preferred embodiments described herein.

Throughout the description and the claims the word understand and include and its variations are not understood to exclude other technical characteristics or components.

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Summary of invention

The present invention is defined by the claims and any matter outside the scope of the claims is provided for informational purposes only. The present invention was carried out in order to overcome the disadvantages mentioned in the prior art and it is the object of the present invention to provide macromolecular complexes of transition metals characterized by having the general formula (I):

(D represented by the molecular formula [M (CpR) XYZ], where:

M is ruthenium, iron, rhodium, iridium or osmium;

CpR is cyclopentadienyl when R is H or substituted cyclopentadienyl, R being selected from: a biomolecule, preferably selected from amino acids, peptides, oligopeptides, proteins, protein fragments, estradiol and its derivatives, vitamins, carbohydrates, water, nucleic acids, a heteroaromatic ligand, a bioactive compound or a radical -Ri, -R1-NH2, -Ri-CCOH, -Ri-COO-, -RiOH, -R1-COONCH3, where Ri is an alkyl or aryl group ; the R groups can be attached to the cyclopentadienyl ring by any of the ring carbons. R can occupy more than one carbon atom, which may give rise to a cyclopentadienyl ring substituted at positions 1, 2, 3, 4 and / or 5;

one of the ligands X, Y or Z is a macroligand, which can itself be a heteroaromatic ligand, X, Y and Z can be selected from heteroaromatic, macroligand, CO, dimethylsulfoxide, a biomolecule or a molecule with biological interest, preferably selected

6/59 between sugars, estrogen, molecules comprising π-conjugated systems, with the following conditions:

- at least one of X, Y or Z is a heteroaromatic ligand, CO or dimethylsulfoxide; and

- at least one of the ligands X, Y or Z comprises or is a biomolecule or molecule with biological interest;

and one of the following conditions:

X, Y and Z are any suitable monodentate ligands, preferably selected from phosphates; heteroaromatic molecules in which the heteroatom can be any suitable heteroatom, and is preferably selected from 0, S, P, N or Se; CO; dimethyl sulfoxide; acetonitrile; nitriles; isonitriles; dimethylformamide; a biomolecule or a molecule of biological interest and at least one of X, Y or Z includes a macroligand; or

X and Y together represent any suitable bidentate macroligand preferably selected from macromolecular diphosphanes, macromolecular heteroaromatic molecules having at least one methylene-oxy or amino-oxy function in the heteroaromatic ring (s), macromolecular oxalates or glycinates macromolecular and Z is any suitable monodentate ligand preferably selected from phosphates, heteroaromatic molecules in which the heteroatom can be any suitable heteroatom and is preferably selected from 0, S, P, N or Se; CO; dimethyl sulfoxide; acetonitrile; nitriles; isonitriles; or dimethylformamide;

X and Y together represent any suitable bidentate ligand preferably selected from diphosphanes, heteroaromatic molecules, oxalates, glycinates, trimethylethylenediamine, ethylenediamine, a biomolecule or a molecule of biological interest, and Z is any

7/59 suitable monodentate ligand preferably selected from macromolecular phosphanes, macromolecular heteroaromatic molecules in which the heteroatom can be any suitable heteroatom and is preferably selected from 0, S, P, N or Se; macromolecular nitriles; or macromolecular isonitriles; and their pharmacologically acceptable salts.

Macroligands, macromolecular monodentate ligands and macromolecular bidentate ligands are molecules with a molecular weight> 1000 g / mol, linear or branched, comprising a repeating unit, and have at least one or more ends functional groups that allow their coordination to a metal center and optionally have biomolecules at one of their ends, preferably selected from amino acids, peptides, oligopeptides, proteins, protein fragments, estradiol and its derivatives, vitamins, carbohydrates, water, nucleic acids, or molecules of biological interest. In one embodiment the macroligands are natural or synthetic polymers of straight or branched chain, containing one or more repeating units preferably selected from polylactide, polycaprolactone, poly-N- (2-hydroxypropyl) methacrylamide, poly (γ, L-glutamic acid ), poly (citric acid), poly (ethylene glycol), poly (aspartic acid); copolymers preferably selected from poly (γ, L-glutamic acid) -citric acid, poly (ethylene glycol) -blocopoly (glutamic acid), poly (ethylene glycol) -block-poly (aspartic acid), poly (ethylene glycol) -poly ( lactic acid), poly (ethylene glycol) -poly (caprolactone); or biopolymers, natural or synthetic, preferably selected from cellulose, starch, chitin, proteins, peptides, DNA and RNA.

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Metal salts are halide, nitrite, phosphate, perchlorate or carbonate salts.

In one aspect, the present invention has the object of bidentated macroligands of general formula (XIV):

(XIV) monodentate macroligands of general formula (XV):

Z ΛΛΛΛΛΛΛΛΛΑ ^ Ο?

w _(xv) as defined in the appended claims.

In another aspect, the present invention relates to the process of synthesizing the complexes of the present invention, including macroligands, as defined in the appended claims.

Other objects of the present invention are pharmaceutical compositions and medicaments comprising a pharmaceutically effective amount of at least one macromolecular transition metal organometallic complex of formula (I), (II), (III) or (IV), as well as their use as medicament, optionally with other active ingredients and / or with pharmaceutically acceptable carriers and / or excipients, as defined in the appended claims.

As defined in the appended claims, the transition metal macromolecular organometallic complexes and the pharmaceutical compositions containing them, according to the present invention can be used as anti-tumor agents and / or as radiosensitizing agents for cancer therapy and / or prevention cancer, in particular for use in the treatment of solid, liquid and / or metastatic tumors. The route

9/59 administration can be topical, intravenous, subcutaneous or intraperitoneal.

These and other advantages of the present invention will become more evident and will be better understood using the figures, description and attached claims that follow. However, the following examples and drawings are presented by way of example and are not intended to limit the present invention. In addition, the present invention covers all possible combinations of the particular and preferred embodiments described herein.

Brief description of the drawings

Figures la) to If) are graphs showing the chemical stability in aqueous media, respectively, of compounds 1, 2, 3, 4, 5 and 6.

Figures 2a) to 2f) are graphs showing the results of gel permeation chromatography, respectively, for compounds 1, 2, 3, 4, 5 and 6.

Figures 3a) and 3b) are graphs depicting the cytotoxic activity of compounds 5 and 6 in human tumor cells of MCF-7 breast adenocarcinoma, after 24 h and 72 h of incubation, respectively.

Figures 4a) and 4b) are dose-response graphs depicting the cytotoxic activity of compounds 5 and 6, after 72 h of incubation, in human A2780 ovarian carcinoma cells and in human breast carcinoma cells MDAMB-231, respectively .

Figures 5a) to 5d) are graphs depicting the cytotoxic activity in human tumor cells of compounds 1, 2, 3, 4 after 48 h of incubation for human tumor lines of ovary A2780, breast MCF-7, glioma U87 and A345 melanoma, respectively,

10/59 where A corresponds to 100 μΜ, B corresponds to 50 μΜ and C corresponds to 10 μΜ.

Figure 6 is a graph representing the cell distribution for compounds 5 (letter A) and 6 (letter B) in human breast tumor cells MCF-7 after 24 h of incubation.

Figure 7 is a graph depicting the results of apoptotic processes in human breast cancer cells MCF-7 not treated and treated with compounds 5 and 6, where A is SMAC diablo and B is catalase.

Figure 8 are graphs depicting the results of assays for determining the type of cell death mechanism induced by compounds 5 and 6 in MCF-7 tumor cells after 48 h of incubation.

Figure 9 is a graph depicting the results of the immunofluorescence assays on human breast cancer cells MCF-7 for determining the effects of compounds 5 and 6 on the cytoskeleton.

Detailed description of the invention

The terms macrolinking, macromolecular monodentate ligand and macromolecular bidentate ligand refer to a molecule of relatively high molecular weight (> 1000 g / mol), natural or synthetic, which has a straight or branched chain containing a repeating unit, and which has at least at one of its ends one or more functional groups which allows (m) its coordination to a metallic center (s) and which can also present at one of its ends biomolecules or molecules of biological interest as defined below. Polymers, which are also understood as copolymers or biopolymers, natural or synthetic, constituents of macroligands are defined below.

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By monomer of interest is meant any small molecule that can bind to other monomers forming larger molecules called (co) polymers.

The term polymerization, which also includes copolymerization (s), should be understood as the chemical reaction that gives rise to (co) polymers.

Polymer refers to a molecule, natural or synthetic, which has a linear or branched chain in its structure, containing one or more repeating units called monomers. Preferred but non-limiting examples of polymers are polylactide, polycaprolactone, poly-N- (2hydroxypropyl) methacrylamide, poly (γ, L-glutamic acid), poly (citric acid), poly (ethylene glycol), poly (aspartic acid), among others . In the description of the synthetic processes and in the formulas (I) to (IV) according to the invention, the term polymer also includes copolymers or biopolymers, whether natural or synthetic.

By copolymer is meant a polymer formed by different monomers. Preferred but non-limiting examples of copolymers include poly (γ, L-glutamic acid) -citric acid, poly (ethylene glycol) -block-poly (glutamic acid), poly (ethylene glycol) -block-poly (aspartic acid), poly (ethylene glycol) ) -poly (lactic acid), poly (ethylene glycol) poly (caprolactone).

In the context of polymerization, a catalyst is understood to mean a molecule that increases the speed of a chemical reaction without being consumed. The catalyst enters the reaction but is regenerated at the end of each reaction cycle. Therefore, a catalyst unit results in the conversion of several reagent units. The catalyst must be distinguished from the initiator. The initiator starts a chain of reactions, but is consumed in the reaction. It is not a catalyst. (IUPAC - Manual of Symbols and Terminology for Physicochemical

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Quantities and Units. Prepared for publication by Robert L. Burwell, Jr. Pergamon Press).

By biopolymers, natural or synthetic are polymers that are produced by living beings or polymers that mimic biopolymers, obtained by chemical processes; preferred, but not limiting, examples of biopolymers are cellulose, starch, chitin, proteins, peptides, DNA and RNA.

By biomolecule is meant any chemical compound in living beings or a molecule that mimics a biomolecule, synthesized by chemical processes; preferred but not limiting biomolecules are amino acids, peptides, oligopeptides, proteins, protein fragments, estradiol and its derivatives, vitamins, carbohydrates, water, nucleic acids, among others. Some biomolecules, due to their chemical structure containing heteroaromatic atoms, may themselves be understood as a heteroaromatic ligand.

Molecule with biological interest is understood to mean any natural or synthetic molecule with potential bioactivity. A compound is considered to be bioactive if it has an interaction or effect with any living cell tissue.

By heteroaromatic ligand is meant any molecule with a single or multiple ring system in which at least one of the rings has at least one hetero atom, such as N, 0, S, Se, P, between others.

By monodentate ligand is meant any molecule that has an electronically available atom to make coordinating bonds to the transition metal; are preferred but not exclusive monodentate ligands, phosphates, heteroaromatic molecules (whose heteroatom can be 0, S, P, N, Se, among others), CO, dimethylsulfoxide,

13/59 acetonitrile, nitriles, isonitriles, dimethylformamide, among others.

By bidentate ligand is meant any molecule that has two atoms with electronic availability to make coordinating connections to the same metallic center; are preferred but not exclusive bidentated ligands, diphosphanes, heteroaromatic molecules, oxalates, glycinate, trimethylethylenediamine, ethylenediamine, among others.

Metal salts (MX3) means halide, nitrite, phosphate, perchlorate and carbonate salts, represented by X, and by metal, any suitable transition metal, in particular ruthenium, iron, rhodium, iridium or osmium, represented by M .

It was found that the best results are obtained using the compounds of the present invention with the general structural formula (I) as antitumor agents:

represented by the molecular formula [M (CpR) XYZ], where:

M is ruthenium, iron, rhodium, iridium or osmium;

CpR is cyclopentadienyl when R is H or substituted cyclopentadienyl, R being selected from: a biomolecule, a heteroaromatic ligand, a bioactive compound or a radical -Ri, -R1-NH2, -Ri-CCOH, -RiC00-, -Ri- OH, -R1-COONCH3, where RI is an alkyl or aryl group; the R groups can be attached to the cyclopentadienyl ring by any of the ring carbons. R can occupy more than one carbon atom, which may give rise to a cyclopentadienyl ring substituted at positions 1, 2, 3, 4 and / or 5;

14/59 one of the ligands X, Y or Z is a macroligand, which can itself be a heteroaromatic ligand, X, Y and Z being selected from heteroaromatic, macroligand, CO, dimethylsulfoxide, a biomolecule or a molecule with biological interest with the following conditions:

at least one of X, Y or Z is a heteroaromatic ligand, CO or dimethylsulfoxide; and at least one of the ligands X, Y or Z comprises or is a biomolecule or molecule of biological interest;

and one of the following conditions:

X, Y and Z are any suitable monodentate ligands, preferably selected from phosphates; heteroaromatic molecules in which the heteroatom can be any suitable heteroatom, and is preferably selected from 0, S, P, N or Se; CO; dimethyl sulfoxide; acetonitrile; nitriles; isonitriles; dimethylformamide; a biomolecule or a molecule of biological interest and at least one of X, Y or Z includes a macroligand; or

X and Y together represent any suitable bidentate macroligand preferably selected from macromolecular diphosphanes, macromolecular heteroaromatic molecules having at least one methylene-oxy or amino-oxy function in the heteroaromatic ring (s), macromolecular oxalates or glycinates macromolecular and Z is any suitable monodentate ligand preferably selected from phosphates, heteroaromatic molecules in which the heteroatom can be any suitable heteroatom and is preferably selected from 0, S, P, N or Se;

15/59

CO; dimethyl sulfoxide; acetonitrile; nitriles; isonitriles; or dimethylformamide;

X and Y together represent any suitable bidentate ligand preferably selected from diphosphanes, heteroaromatic molecules, oxalates, glycinates, trimethylethylenediamine, ethylenediamine, a biomolecule or molecule of biological interest, and Z is any suitable monodentate ligand selected preferably from phosphates. macromolecular, macromolecular heteroaromatic molecules in which the heteroatom can be any suitable heteroatom and is preferably selected from 0, S, P, N or Se; macromolecular nitriles; or macromolecular isonitriles.

Thus, in an aspect of the present invention, a group of particularly preferred compounds of formula (I) is that represented by general formula (II):

(II) in which

R is H;

M represents ruthenium or iron;

X and Y together represent a bidentate macroligand having at least one methylene-oxy or amino-oxy function in the heteroaromatic ring (s), preferably containing at its end one or more molecules of biological interest or a biomolecule;

16/59

Z represents phosphane, CO, dimethylsulfoxide, a monodentate heteroaromatic ligand, a molecule with biological interest or a ligand including a molecule with biological interest or biomolecule;

a represents polymer; and b represents a molecule of biological interest.

Another particularly preferred group of compounds of formula (I) is represented by the general formula (III):

in which

R is H;

M represents ruthenium or iron;

X and Y represent heteroaromatic or together a bidentate ligand molecule of biological interest or biomolecule;

Z represents a macromolecular monodentate phosphate ligand, which at its end may contain a molecule of biological interest or a biomolecule;

a represents a polymer; and b represents a molecule of biological interest.

Another particularly preferred group of compounds of formula (I) is represented by the general formula (IV):

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in which

R is H;

M represents ruthenium or iron;

Z represents a monodentate macroligand, in which the polymer is preferably linked to a phosphate or a heteroaromatic ligand, and at its end may contain a molecule of biological interest;

Y preferably represents CO;

X represents a halide, a ligand of biological interest or a biomolecule;

a represents a polymer; and b represents a molecule of biological interest or a biomolecule.

The compounds of formula (I) can be cationic or neutral and can be presented in the form of salt, the anions of which can be, for example, halides, phosphates, triflates, phenylborates, hexafluorophosphates, among others.

Especially preferred compounds according to the present invention are the following compounds:

(2,2'-Bipyridine-4,4'-diylbis {methylene} bis (2— {2— (2-hydroxypropanoyloxy) poly (lactic acid) -ylJpropanoate) -k ² N, Ν ') hexafluorophosphate (η ⁵ cyclopentadienyl) ruthenium (II) (Compound 1) of formula (V):

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[(1,1 '- {1,1' - (1,1 '- {2,2'-bipyridine hexafluorophosphate

4,4'-di-ilbis (methylene)} bis (oxy) bis (l-oxopropane-2,1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2 , 1-di-yl) dianthracene-9-carboxylate) -k ² N, Ν '] (carbonyl) (η ⁵ cyclopentadienyl) ruthenium (II) (VI):

(Compound 2) of formula

(SAW)

[(1,1 '- {1,1' - (1,1 '- {2,2'-bipyridine-4,4'-diylbis (methylene)} bis (oxy) bis (l-oxopropane-2) triflate , 1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-diyl) dianthracene-9-carboxylate) k ² N, N '] (triphenylphosphane) (r | ^5- cyclopentadienyl) ruthenium (11)) (Compound 3) of formula (VII):

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[(1, 1 '- {1, 1' - (1,1 '- {2,2'-bipyridine-4,4'-diylbis (methylene)} bis (oxy) bis (l-oxopropane-2) triflate , 1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-diyl) dinaphthalene-2-carboxylate) k ² N, N '] (triphenylphosphane) (r | ^5- cyclopentadienyl) ruthenium (11) (Compound 4) of formula (VIII):

(2,2'-Bipyridine-4,4'-di-ylbis {methylene} bis (2 {2- (2-hydroxypropanoyloxy) poly (lactic acid) ylpropanoate) -k ² N, Ν ') (triphenylphosphane) triflate (η ⁵ cyclopentadienyl) ruthenium (II) (Compound 5) of formula (IX):

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[(1, 1 '- {1, 1' - (1,1 '- {2,2'-bipyridine-4,4'-diylbis (methylene)} bis (oxy) bis (l-oxopropane-2) triflate , 1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-di-yl) di (2S, 3S, 4S, 5R, 6R) -3.4 , 5,6-tetrahydroxyoxane-2 carboxylate) -k ² N, Ν '] (triphenylphosphane) (η ⁵ cyclopentadienyl) ruthenium (II) (Compound 6) of formula (X):

OH

O | Ο ΗΟγλγΟΗ ^{0 0} HO ^ q ^ OH

ÕH (X)

[1 - ({1 - ({1- (Benzyloxy) -l-oxopropane-2-yl} oxy) -1- (poly- (lactic acid))} - 1-oxopropane-2-yl 4- (diphenylphosphino) benzoate-k ¹ ?] (carbonyl) (iodide) (r | ^5- cyclopentadienyl) iron (II) (Compound 7) of formula (XI):

(XI)

[Tris (1— {1— (1-hydroxypropanoyloxy) poly (lactic acid) ylpropanoate) phosphane-k ¹ ?] (Carbonyl) (iodide) (η ⁵ cyclopentadienyl) iron (II) (Compound 8), of formula (XII ):

(XII)

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[(1 - ({1 - ({1- (benzyloxy) -l-oxopropane-2-yl} oxy) 1- (poly- (lactic acid)} - 1-oxopropane-2-yl) -4 ( diphenylphosphino) benzoate-k ¹ ?] ((2-benzoylopyridine) -k ² N, 0) (η ⁵ cyclopentadienyl) ruthenium (II) - (Compound 9), of formula (XIII):

(XIII)

The present invention relates to bidentated macroligands of general formula (XIV):

(XIV) in which

X and Y together represent a macromolecular bidentate phosphate ligand or a macromolecular bidentate heteroaromatic ligand having at least one methylene-oxy or amino-oxy function in the heteroaromatic ring (s), and may preferably contain in their one or more molecules of biological interest or a biomolecule;

a represents polymer;

b represents a molecule of biological interest or biomolecule.

The present invention also relates to monodentate macroligands of general formula (XV):

22/59 to Z ΛΑΜΛΛΛΛΛΛ ^^. ' w (xv) in which

Z represents a monodentate heteroaromatic macromolecular ligand or a monodentate macromolecular phosphane, which may preferably contain at its end one or more molecules of biological interest or a biomolecule;

a represents polymer;

b represents a molecule of biological interest or biomolecule.

Preferred macromolecular bidentated heteroaromatic ligands of the present invention are:

a) l, l '- {l, l' - (l, l '- {2,2'-bipyridine-4,4'-diylbis (methylene)} bis (oxy) bis (l-oxopropane-2 , 1-di11)) bis (poly (lactic acid) -11))} bis (oxy) bis (1-oxopropane-

2,1-di-yl) dianthracene-9-carboxylate of formula (XVI):

b) l, l '- {l, l' - (l, l '- {2,2'-bipyridine-4,4'-diylbis (methylene)} bis (oxy) bis (l-oxopropane-2 , 1-diyl)) bis (poly (lactic acid) -11))} bis (oxy) bis (1-oxopropane-

2,1-di-yl) dinaphthalene-2-carboxylate of formula (XVII):

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(XVII)

c) -bipyridine-4,4'-di-ylbis (methylene)} bis (oxy) bis (l-oxopropane-2,1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-di-yl) di (2S, 3S, 4S, 5R, 6R) -3,4,5,6-tetrahydroxyoxane-2carboxylate of formula (XVIII):

(XVIII)

Preferred macromolecular monodentative phosphate ligands of the present invention are:

d) l - ({l - ({l- (benzyloxy) -l-oxopropane-2-yl} oxy) -1 (poly- (lactic acid))} - l-oxopropane-2-yl 4 (diphenylphosphino) benzoate formula (XIX):

(XIX)

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e) tris (1- {1- (1-hydroxypropanoyloxy) poly (lactic acid) -ylpropanoate) phosphane of formula (XX):

(XX)

In another aspect, the objectives of the present invention are processes for the synthesis of new organometallic compounds.

Step 1) Synthesis of macroligands

a) Synthesis of heteroaromatic macroligands

For the synthesis of heteroaromatic macroligands, proceed as follows:

i) A heteroaromatic ligand, selected from pyridines, bipyridines, imidazoles, among others, containing, for example, a primary alcohol or amine function, acts as an initiator and / or catalyst for the polymerization of the monomer (s) of interest, to obtain the heteroaromatic macroligand. The heteroaromatic macroligand obtained can be purified, if necessary, by the usual purification techniques and linked to a molecule of biological interest (eg sugars, estrogen, molecules containing π-conjugated systems, among others) through condensation, substitution, addition, elimination reactions , pericyclic, rearrangement or redox.

ii) A previously prepared or commercially available polymer is reacted through condensation, substitution, addition, elimination, pericyclic, rearrangement or redox reactions with a heteroaromatic ligand (e.g. pyridines, bipyridines, imidazoles, among others). The obtained heteroaromatic macroligand can be purified, if necessary, by the usual purification techniques and linked to a molecule

25/59 with biological interest through condensation, substitution, addition, elimination, pericyclic, rearrangement or redox reactions (eg sugars, estrogen, molecules containing π conjugated systems, N- (3- {[5- (4-chlorophenyl) - IH-pyrrolo [2,3b] pyridine-3-yl] carbonyl} -2,4-difluorophenyl) propane-1sulfonamide, bromocriptine, 4-methyl-5-oxo-2,3,4,6,8pentazabicyclo [4.3.0 ] ninth-2,7,9-triene-9-carboxamide, among others.

iii) A molecule of biological interest (e.g. amino acids, DNA bases, among others) containing, for example, an amine or primary alcohol function, serves as an initiator and / or catalyst for the polymerization of the monomer (s) of interest. The macromolecule obtained can be purified, if necessary, by the usual purification techniques and linked to a heteroaromatic ligand (eg pyridines, bipyridines, imidazoles, among others) through condensation, substitution, addition, elimination, pericyclic, rearrangement or redox reactions, originating the heteroaromatic macroligand.

iv) A previously prepared or commercially available polymer is reacted through condensation, substitution, addition, elimination, pericyclic, rearrangement or redox reactions with a molecule of biological interest (eg sugars, estrogen, molecules containing π conjugated systems, N- ( 3 {[5- (4-chlorophenyl) -IH-pyrrolo [2,3-b] pyridine-311] carbonyl} -2,4-difluorophenyl) propane-1-sulfonamide, bromocriptine, 4-methyl-5-oxo- 2,3,4,6,8 pentazabiciclo [4.3.0] nona-2,7,9-triene-9-carboxamide among others). This macromolecule can be purified, if necessary, by the usual purification techniques and linked to a heteroaromatic ligand through condensation, substitution, addition, elimination, pericyclic reactions, rearrangement or redox, giving rise to the heteroaromatic macroligand (eg pyridines, bipyridines, imidazoles, among others).

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b) Synthesis of macromolecular phosphates

For the synthesis of macromolecular phosphates, one of the following can be done:

i) A phosphane containing, for example, an alcohol or primary amine function, serves as an initiator and / or catalyst for the polymerization of the monomer (s) of interest, to obtain macromolecular phosphane. The macromolecular phosphane obtained can be purified, if necessary, by the usual purification techniques and linked to a molecule of biological interest (eg sugars, estrogen, molecules containing π conjugated systems, N- (3 - {[5- (4-chlorophenyl) -IH-pyrrole [2,3—

b] pyridine-3-yl] carbonyl} -2,4-difluorophenyl) propane-1sulfonamide, bromocriptine, 4-methyl-5-oxo-2,3,4,6,8pentazabicyclo [4.3.0] nona-2.7 , 9-triene-9-carboxamide among others) through condensation, substitution, addition, elimination, pericyclic, rearrangement or redox reactions.

ii) A phosphane is reacted with a previously prepared or commercially available polymer, through condensation, substitution, addition, elimination, pericyclic, rearrangement or redox reactions to give macromolecular phosphane. After being purified, if necessary, by the usual purification techniques, macromolecular phosphane may be linked to a molecule of biological interest (eg sugars, estrogen, molecules containing π-conjugated systems, among others) through condensation, substitution, addition, elimination, pericyclic, rearrangement or redox.

iii) A molecule of biological interest (eg sugars, estrogen, molecules containing π-conjugated systems, among others) containing, for example, a primary alcohol or amine function, serves as an initiator and / or catalyst for the polymerization of the monomer (s) ) of interest to obtain the macroligand. This macromolecule can be purified, if necessary, by

27/59 usual purification techniques and linked to a phosphate through condensation, substitution, addition, elimination, pericyclic reactions, rearrangement or redox, giving rise to macromolecular phosphane.

iv) A previously prepared or commercially available polymer is reacted, through condensation, substitution, addition, elimination, pericyclic, rearrangement or redox reactions, with a molecule of biological interest (eg sugars, estrogen, molecules containing conjugated π systems, N- (3 - {[5- (4-chlorophenyl) -IH-pyrrole [2,3—

b] pyridine-3-yl] carbonyl} -2,4-difluorophenyl) propane-1sulfonamide, bromocriptine, 4-methyl-5-oxo-2,3,4,6,8pentazabicyclo [4.3.0] nona-2.7 , 9-triene-9-carboxamide among others). This macromolecule can be purified, if necessary, by the usual purification techniques and linked to a phosphate through condensation, substitution, addition, elimination, pericyclic, rearrangement or redox reactions, giving rise to macromolecular phosphate.

Step 2) Synthesis of macromolecular organometallic complexes of transition metals:

i) For the synthesis of complexes of the present invention of general formula (I) in which

X and Y represent two macromolecular monodentate phosphate ligands and Z is a monodentate heteroaromatic ligand, CO, dimethyl sulfoxide, a biomolecule or a molecule of biological interest; or

X and Y together represent a macromolecular bidentate phosphate ligand and Z is a monodentate heteroaromatic ligand, CO, dimethylsulfoxide, a biomolecule or a molecule of biological interest; or

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X is a macromolecular monodentate phosphate ligand and Y and Z together represent a bidentate heteroaromatic ligand, a biomolecule or a molecule with biological interest, a compound of formula [M (CpR) (PP) L] is reacted in which PP represents two macromolecular phospho-s-monodentate ligands or a macromolecular bidentate phosphate ligand, L is a halide, such as chloride or iodide, with a heteroaromatic, mono or bidentate LI ligand, CO, dimethyl sulfoxide, a biomolecule or a molecule with biological interest.

ii) For the synthesis of complexes of the present invention of general formula (I) in which

X and Y represent two monodentate phosphate ligands, Z is a monodentate macromolecular heteroaromatic ligand; or

X and Y together represent a bidentate phosphate ligand, Z is a monodentate macromolecular heteroaromatic ligand; or

X is a monodentate phosphate ligand; Y and Z together represent a bidentated macromolecular heteroaromatic ligand having at least one methylene oxy or aminooxy function in the heteroaromatic ring (s), a macromolecular heteroaromatic ligand is reacted with a [M ( CpR) (PP) L] where PP represents two monodentate phosphate ligands or a bidentate phosphate ligand; L is a halide, such as chloride or iodide.

iii) For the synthesis of complexes of the present invention of general formula (I) in which

X and Y represent two macromolecular monodentate phosphate ligands, Z is a heteroaromatic ligand

29/59 monodentate, CO, dimethyl sulfoxide, a biomolecule or a molecule with biological interest; or

X and Y together represent a macromolecular bidentate phosphate ligand, Z is a monodentate heteroaromatic ligand, CO, dimethylsulfoxide, a biomolecule or a molecule of biological interest; or

X is a macromolecular monodentate phosphate ligand; Y and Z together represent a bidentated heteroaromatic ligand, a biomolecule or a molecule of biological interest, direct reaction of a metal salt (MX3, hydrated or unhydrated) with the cyclopentadienyl derivative (CpR) and an excess of macromolecular phosphane. After purification of the compound obtained of the general formula [M (CpR) (PP) L] (where PP represents two macromolecular monodentate phosphate ligands or a macromolecular bidentate phosphate ligand; L is a halide, such as chloride or iodide), as follows if a substitution reaction of the halide (and possibly a macromolecular phosphate) with a mono or bidentate heteroaromatic ligand, CO, dimethyl sulfoxide, a biomolecule or a molecule with biological interest, to obtain a final compound with the formula [M (CpR) X Y Z].

iv) For the synthesis of complexes of the present invention of general formula (I) in which

X and Y represent two macromolecular monodentate phosphate ligands, Z is a monodentate heteroaromatic ligand, CO, dimethylsulfoxide, a biomolecule or a molecule of biological interest; or

X and Y together represent a macromolecular bidentate phosphate ligand, Z is a monodentate heteroaromatic ligand, CO, dimethylsulfoxide, a biomolecule or a molecule of biological interest; or

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X is a macromolecular monodentate phosphate ligand; Y and Z together represent a bidentated heteroaromatic ligand, a biomolecule or a molecule of biological interest, direct reaction of a metal salt (MX3), hydrated or unhydrated) with the cyclopentadienyl derivative (CpR) and an excess of phosphane containing a functional group that allows later functionalization, such as the carboxyl group. After purification of the compound obtained of the general formula [M (CpR) (PP) L] (where PP represents two monodentate phosphate ligands containing a functional group or a bidentate phosphate ligand containing a functional group; L is a halide, such as chloride or iodide), a reaction of substitution of the halide (and possibly a phosphate containing a functional group) is followed by a mono or bidentate heteroaromatic ligand, CO, dimethylsulfoxide, a biomolecule or a molecule of biological interest. Then, the obtained compound is reacted with a previously prepared or commercially available polymer, through condensation, substitution, addition, elimination, pericyclic, rearrangement or redox reactions, to obtain a final compound with the formula [M (CpR) X Y Z]. v) For the synthesis of complexes of the present invention of general formula (I) in which

X and Y represent two macromolecular monodentate phosphate ligands, Z is a monodentate heteroaromatic ligand, CO, dimethylsulfoxide, a biomolecule or a molecule of biological interest; or

X and Y together represent a macromolecular bidentate phosphate ligand, Z is a monodentate heteroaromatic ligand, CO, dimethylsulfoxide, a biomolecule or a molecule of biological interest; or

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X is a macromolecular monodentate phosphate ligand; Y and Z together represent a bidentated heteroaromatic ligand, a biomolecule or a molecule of biological interest; or

X and Y represent two monodentate phosphate ligands, Z is a monodentate macromolecular heteroaromatic ligand; or X and Y together represent a bidentate phosphate ligand, Z is a monodentate macromolecular heteroaromatic ligand; or

X is a monodentate phosphate ligand; Y and Z together represent a bidentated macromolecular heteroaromatic ligand having at least one methylene-oxy or amino-oxy function in the heteroaromatic ring (s), a macromolecular ligand is reacted with a [M (CpR ) (NCMe) 3] ⁺ [W] - with substitution of 1 or 2 acetonitriles according to the options given above. Then, without isolating this compound, the reaction is carried out with the other ligand (s) of interest (mono or bidentate heteroaromatic ligand, mono or bidentate phosphane, a biomolecule or a molecule with biological interest), to obtaining the compound with the desired formula [M (CpR) XYZ] ⁺ [W] ~ (where W is an anion preferably selected from PFe, CF3SO3, Cl, I, BPh4, among others).

vi) For the synthesis of complexes of the present invention of general formula (I) in which

X and Y represent two macromolecular monodentate phosphate ligands, Z is a monodentate heteroaromatic ligand, CO, dimethylsulfoxide, a biomolecule or a molecule of biological interest; or

X is a macromolecular monodentate phosphate ligand, Y and Z represent monodentate heteroaromatic ligands, CO,

32/59 dimethylsulfoxide, biomolecule or molecule with biological interest reaction between the metal salt (MX3), hydrated or not hydrated, L is a halide such as chloride or iodide, and an excess macromolecular phosphane, giving rise to the compound [Ru ( macromolecular phosphane) 3L _n ] (n is 2 or 3). Subsequently, this compound is reacted with (CpRJNa ^ or (CpR) in the presence of KOBut, giving rise to the compound [M (CpR) (PP) L] (PP represents two macromolecular monodentinated phosphate ligands). eventually a macromolecular phosphane) is (are) replaced (s) with a mono or bidentate heteroaromatic ligand (s), CO, dimethylsulfoxide, a biomolecule or a molecule with biological interest to obtain a final compound with the formula [M (CpR) XYZ].

vii) For the synthesis of complexes of the present invention of general formula (I) in which

X and Y together represent a macromolecular bidentate phosphate ligand, Z is a monodentate heteroaromatic ligand, CO, dimethylsulfoxide, a biomolecule or a molecule with biological interest reaction between [Ru (PPhs) 3Cl _n ] where n is 2 or 3 and one macromolecular bidentate phosphane giving the compound [Ru (macromolecular bidentate phosphate) 2Cl _n ] (n is 2 or 3). Subsequently, this compound is reacted with (CpRJNa ^ or (CpR) in the presence of KOBut, giving rise to the compound [M (CpR) (PP) L] (PP is macromolecular bidentate phosphate; L is a halide). L is replaced by a monodentate heteroaromatic ligand, CO, dimethylsulfoxide, a biomolecule or a molecule of biological interest to obtain a final compound with the formula [M (CpR) XYZ].

Viii) For the synthesis of complexes of the present invention of general formula (I) in which

X and Y represent two macromolecular monodentate phosphate ligands, Z is a monodentate heteroaromatic ligand, CO, a halide, dimethyl sulfoxide, a biomolecule or a molecule of biological interest; or X is a macromolecular monodentate phosphate ligand, Y and Z represent monodentate heteroaromatic ligands, CO, halide, dimethylsulfoxide, biomolecule or molecule with biological interest reaction between [M (CpR) (CO) 2L] where L is a halide, as per example chloride or iodide, and a macromolecular phosphane to give a complex of the type [M (CpR) X (CO) L] where X is a monodentate macromolecular phosphate, L is a halide. One or both of CO and L can be replaced by a monodentate heteroaromatic ligand, CO, a halide, dimethyl sulfoxide, a biomolecule or a molecule with biological interest, to obtain a final compound with the formula [M (CpR) XYZ].

ix) For the synthesis of complexes of the present invention of general formula (I) in which

X and Y together represent a macromolecular bidentate phosphate ligand, Z is a monodentate heteroaromatic ligand, CO, a halide, dimethyl sulfoxide, a biomolecule or a molecule with biological interest, reaction between [M (CpR) (CO) 2L] where L it is a halide, and a macromolecular bidentate phosphate to give a compound of formula [M (CpR) XYL] where X and Y together represent a macromolecular bidentate phosphate ligand and L is a halide). L is then replaced by a monodentate heteroaromatic ligand, CO, dimethylsulfoxide, a biomolecule or a molecule of biological interest.

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These compounds, having the same general structure, and the same 'M (CpR)' fragment allow a very careful synthesis of polymers and molecules of biological interest for the intended purpose, since the syntheses performed have a high degree of yield (70 -90%) and, in most cases, without the need for additional purifications. The products are obtained with a degree of purity between 80-95%, suitable for use as drugs, as can be seen by the monomodal character of the chromatograms obtained by gel permeation chromatography (Figures 2a to 2f) and by the dispersivity values included between 1.1 - 1.4 (also calculated from the same chromatograms). Nuclear magnetic resonance allows the calculation of the percentage of functionalization that is between 80-95% as already mentioned.

The reaction medium for all the inorganic / organometallic syntheses described above comprises a solvent or a mixture of solvents selected from water, ethanol, methanol, ethyl acetate, isopropanol, tertbutanol, ethylene glycol, dimethylglioxima, diethyl ether, chloroform, dichloromethane, benzene, toluene, acetone, tetrahydrofuran, dimethyl sulfoxide, dioxane, dimethylformamide or acetonitrile.

The procedures described above can take place at temperatures between -80 ° C and 300 ° C, and the pressure between 10 ~ ³ at 100 atm, with or without agitation, with irradiation by UV light, and with the addition of a salt whenever necessary .

The complexes of the present invention are stable in air and in an aqueous medium for a suitable period of time for medicinal purposes and have very relevant anti-tumor and anti-metastatic properties.

Thus, and in another aspect, the present invention relates to pharmaceutical compositions and drugs that

35/59 comprise a pharmaceutically effective amount of at least one macromolecular transition metal complex of the present invention or a salt thereof, optionally in association with other active ingredients and / or with pharmaceutically acceptable vehicles and / or excipients.

The macromolecular organometallic complexes of transition metals of formula (I), (II), (III) or (IV) as defined above and the compositions and medicaments according to the invention can be used for example in the treatment of tumors, either main tumor, or metastases, originating from it. Examples of tumors are breast carcinomas, carcinoma of the ovary, prostate, pancreas, glioma, leukemia and melanoma, among others. They can also be used in photodynamic therapy to treat superficial cancers such as skin cancer, pharynx, among others.

In yet another aspect, the present invention relates to the use of the compounds of formula (I) in medicine, namely in the treatment and / or prevention of cancer, including the treatment of solid, liquid and / or metastatic tumors. In addition, the compounds of the present invention can be used in pharmaceutical compositions or medicaments as antitumor agents and / or as radiosensitizing agents for cancer therapy.

The following particular examples are intended only to illustrate the present invention should not be construed as limitations of the present invention.

Examples

I - Summary

Example 1

Synthesis of a heteroaromatic macroligand: 2,2'-bipyridine

4,4'-di-ilbis {methylene} bis (2- {2- (2 hydroxypropanoyloxy) poly (lactic acid) -yl} propanoate)

36/59

The synthesis was carried out using Schlenk techniques under an inert nitrogen atmosphere and the solvents were previously dried and distilled under a nitrogen atmosphere. A mixture of 1 g of 3,6-dimethyl-1,4-dioxane-2,5-dione, 56.5 mg of dimethylaminopyridine and 37.5 mg of 2,2'-bipyridine-4,4'dimethanol was heated to 135 ° C in an oil bath under agitation. After fusion of 3,6-dimethyl-1,4-dioxane-2,5-dione, 5 minutes were waited, and at the end of this time the reaction was stopped with the addition of an excess of a methanol / water mixture. Then, the product was precipitated in about 50 ml of a methanol / water mixture. The solvent was evaporated in vacuo and the product obtained was washed with diethyl ether and dried in vacuo, thereby obtaining about 750 mg of the title compound as a white product.

¹ H NMR [CD3CI3, Me4Si, δ / ppm (multiplicity, attribution)]: 8.67 [d, Hmeta bipyridine], 8.30 [s, Hortho bipyridine], 7.27 bipyridine], 5.26 [s, -CH2O bipyridine], 5.16 [m , -CH- polylactide main chain], 4.36 [q, -CH- polylactide terminal], 1.55 [m, -CH3 polylactide main chain], 1.49 [m, -CH3 polylactide terminal].

Example 2

Synthesis of a heteroaromatic macroligand functionalized with a molecule of biological interest: 1,1 '- {1,1' - (1,1 '- {2,2'bipyridine-4,4'-di-ilbis (methylene)} bis (oxy) bis (1-oxopropane2,1-di-yl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1oxopropane-2,1-di-yl) dianthracene-9-carboxylate

The synthesis was carried out using Schlenk techniques under an inert nitrogen atmosphere and the solvents were previously dried and distilled under a nitrogen atmosphere. 300 mg of 2,2'-bipyridine-4,4'-di-ylbis {methylene} bis (2- {2- (2hydroxypropanoyloxy) poly (lactic acid) -ylJpropanoate), obtained in example 1, were dissolved in tetra -hydrofuran (THF) anhydrous and

37/59 25 μΐ of triethylamine was added. The reaction proceeded for 1 h. At the end of this time, 36.5 mg of anthracene-9-carboxylic acid was added to the solution and the reaction proceeded at the reflux temperature of the THF until complete removal of the water formed during the reaction using a Dean-Stark assembly. Finally, the obtained compound was dried in vacuo, thereby obtaining about 300 mg of the title compound 1 '{1,1'- (1,1' - {2,2'-bipyridine-4,4'-diylbis ( methylene)} bis (oxy) bis (l-oxopropane-2,1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-di-yl) dianthracene- 9-carboxylate of the title in the form of a white product.

¹ H NMR [CD3CI3, Me4Si, δ / ppm (multiplicity, attribution)]: 8.67 [d, Hmeta bipyridine], 8.38 [d, Hpaz-a anthracene + Hortho bipyridine], 8.16 [d, H-aromatic anthracene], 7.95 [d, Aromatic anthracene], 7.43 [t, H-aromatic anthracene], 7.27 [d, Hpaz-a bipyridine], 5.26 [s, -CH2O bipyridine], 5.16 [m, CH- polylactide main chain], 4.36 [ q, -CH- polylactide terminal], 1.57 [m, -CH3 polylactide backbone], 1.50 [m, -CH3 polylactide terminal].

Example 3

Alternative synthesis of an organometallic ruthenium complex containing a heteroaromatic macroligand: (2,2'-bipyridine-4,4'-di-ylbis {methylene} bis (2- {2- (2hydroxypropanoyloxy) poly (lactic acid) hexafluorophosphate - il} propanoate) k ² N, N ') (carbonyl) (η ⁵ -cyclopentadienyl) ruthenium (II) Compound 1

The synthesis was carried out using Schlenk techniques under an inert nitrogen atmosphere and the solvents were previously dried and distilled under a nitrogen atmosphere. 15 mg of [Ru (Cp) (NCMe) s] [PFe] were dissolved in anhydrous dichloromethane. The obtained solution was cooled to 0 ° C using ice. As soon as

38/59 reached a temperature of 0 ° C, 170 mg of 2,2'bipyridine-4,4'-di-ylbis {methylene} bis (2- {2- (2hydroxypropanoyloxy) poly (lactic acid) - il} propanoate) obtained in example 1. After 5 min, the solution was removed from the ice and allowed to react for about 30 min at room temperature. After this time, a flow of CO was passed for about 15 min. Then the solution was filtered with Celite and the filtrate was evaporated to the limit of precipitation of the compound. About 15 ml of anhydrous hexane was added to force precipitation. The solution was decanted and the precipitate was dried in vacuo. The product was recrystallized from anhydrous dichloromethane / hexane, thus obtaining 150 mg of the compound (2,2'-bipyridine-4,4'-diylbis {methylene} bis (2— {2— (2-hydroxypropanoyloxy) poly hexafluorophosphate (lactic acid) -yl Jpropanoate) -k ² N, Ν ') (carbonyl) (r | ^5- cyclopentadienyl) ruthenium (11) in the form of a brownish salt.

¹ H NMR [acetone-d6, Me4Si, δ / ppm (multiplicity, assignment)]: 9.2 8 [d, Hmeta bipyridine], 8.49 [s, Hozr / w bipyridine], 7.69 bipyridine], 5.51 [s, r | ⁵ -cyclopentadienyl], 5.30 [m, -CH polylactide backbone + -CH2O bipyridine], [q, -CH polylactide end], 1.55 [m, -CH3 polylactide backbone], 1.39 [m, -CH3 polylactide end ].

Example 4

Alternative synthesis of an organometallic ruthenium complex containing a heteroaromatic macroligand: [(1,1 '- {1,1' - (1,1 '- {2,2'-bipyridine-4,4'-diylbis (methylene hexafluorophosphate) )} bis (oxy) bis (l-oxopropane-2,1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-di-yl) diantracene-9 -carboxylate) - k ² N, N '] (carbonyl) (η ⁵ -cyclopentadienyl) ruthenium (II) - Compound 2

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The synthesis was carried out using Schlenk techniques under an inert nitrogen atmosphere and the solvents were previously dried and distilled under a nitrogen atmosphere. 15 mg of [Ru (Cp) (NCMe) sJ [PFe] were dissolved in anhydrous dichloromethane. The obtained solution was cooled to 0 ° C using ice. As soon as it reached 0 ° C, 170 mg of 1,1 '{1,1'- (1,1' - {2,2 '-bipyridine-4,4'-diylbis (methylene)} were added bis (oxy) bis (l-oxopropane-2,1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-di-yl) dianthracene-9-carboxylate obtained in example 2. After 5 min, the solution was removed from the ice and allowed to react for about 30 min at room temperature. After this time, a flow of CO was passed for about 15 min. Then the solution was filtered with Celite and the filtrate was evaporated to the limit of precipitation of the compound. About 15 ml of anhydrous hexane was added to force precipitation. The solution was decanted and the precipitate was dried in vacuo. The product was recrystallized with anhydrous dichloromethane / hexane, thus obtaining about 150 mg of [(1, 1 '- {1.1' - (1,1 '- {2,2'-bipyridine4,4 hexafluorophosphate compound) '-di-ilbis (methylene)} bis (oxy) bis (l-oxopropane-2,1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1- di-yl) dianthracene-9-carboxylate) - k ² N, N '] (carbonyl) (η ⁵ cyclopentadienyl) ruthenium (II) in the form of a brownish salt.

¹ H NMR [acetone-d6, Me4Si, δ / ppm (multiplicity, assignment)]: 8.71 [d, Hmeta bipyridine], 8.62 [s, Hpa ^ a anthracene], 8.49 [s, Hortho bipyridine], 8.22 [d, H-aromatic anthracene], 8.11 [d, Homatic anthracene], 7.55 [m, H-aromatic anthracene], 7.45 [d, bipyridine], 5.38 [s, r | ^5- cyclopentadienyl], 5.21 [m, -CH- polylactide + -CH2O bipyridine main chain], 4.31 [q, -CH- polylactide terminal], 1.55 [m, -CH3 chain

Main polylactide 40/59], 1.39 [m, polylactide terminal -CH3].

Example 5

Alternative synthesis of an organometallic ruthenium complex containing a heteroaromatic macroligand: [(1,1 '- {1,1' - (1,1 '- {2,2'-bipyridine-4,4'-diylbis (methylene triflate) )} bis (oxy) bis (l-oxopropane-2,1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-di-yl) diantracene-9 -carboxylate) - k ² N, N '] (triphenylphosphane) (η ⁵ -cyclopentadienyl) ruthenium (II)) Compound 3

The synthesis was carried out using Schlenk techniques under an inert nitrogen atmosphere and the solvents were previously dried and distilled under a nitrogen atmosphere. 70 mg of [RuCp (PPhs) 2CI] were dissolved in anhydrous dichloromethane. Then 450 mg of 1.1 '- {1.1' - (1.1 '- {2,2'-bipyridine-4,4'dí-Íbís (methylene)} bis (oxy) bis ( 1-oxopropane-2,1-di11)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-di-yl) dianthracene-9-carboxylate obtained in examples 2 and 24.6 mg of AgCFsSOs. The obtained mixture was refluxed for 3 h with stirring. It was allowed to stand and the solution was filtered to remove the precipitated AgCl. The product was then vacuum dried, washed with hexane and recrystallized with anhydrous dichloromethane / hexane, thus obtaining about 430 mg of the [(1,1 '- {1.1' - (1,1'- {2,2'bipyridine-4,4'-di-ibis (methylene)} bis (oxy) bis (1-oxopropane2,1-di-yl)) bis (poly (lactic acid) -yl))} bis ( oxy) bis (loxopropane-2,1-di-yl) dianthracene-9-carboxylate) - k ² N, N '] (triphenylphosphane) (η ⁵ -οίclopentadienyl) ruthenium (II) in the form of a salt of Orange color.

¹ H NMR [acetone-d6, Me4Si, δ / ppm (multiplicity, attribution)]: 9.51 [d, Hmeta bipyridine], 8.49 [m, H-aromatic anthracene +

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Hortho bipyridine], 7.70 [m, H-aromatic anthracene], 7.57 [m, Haromatic phosphate], 7.57 [d, bipyridine], 7.43 [m, Haromatic phosphane], 7.13 [m, H-aromatic phosphate], 5.35 [s , CH2O- bipyridine], 5.21 [m, -CH- polylactide backbone], 4.94 [s, r | ^5- cyclopentadienyl], 4.31 [m, -CH polylactide end], 1.55 [m, -CH3 polylactide backbone], 1.39 [m, -CH3 polylactide end].

Example 6

Alternative synthesis of an organometallic ruthenium complex containing a heteroaromatic macroligand: [(1,1 '{1, 1' - (1, 1 '- {2,2'-bipyridine-4,4'-diylbis (methylene) triflate } bis (oxy) bis (l-oxopropane-2,1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-di-yl) dinafthalene-2- carboxylate) -k ² N, N '] (triphenylphosphane) (η ⁵ -cyclopentadienyl) ruthenium (II) - Compound 4

The synthesis was carried out using Schlenk techniques under an inert nitrogen atmosphere and the solvents were previously dried and distilled under a nitrogen atmosphere. 70 mg of [RuCp (PPhs) 2CI] were dissolved in anhydrous dichloromethane. Then 450 mg of (1,1 '- {1,1' - (1,1 '- {2,2'-bipyridine4,4'-di-ilbis (methylene)} bis (oxy) bis ( 1-oxopropane-2,1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-di-yl) dinaphthalene-2-carboxylate) and 24.6 mg of AgCFsSOs . The obtained mixture was refluxed for 3 h with stirring. It was allowed to stand and the solution was filtered to remove the precipitated AgCl. The product was then vacuum dried, washed with hexane and recrystallized with anhydrous dichloromethane / hexane, thus obtaining about 420 mg of [(1.1 '- {1.1' (l, l '- {2 , 2'-bipyridine-4,4'-diylbis (methylene)} bis (oxy) bis (l-oxopropane-2,1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane

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2., 1-di-yl) dinaphthalene-2-carboxylate) k ² N, N '] (triphenylphosphane) (r | ^5- cyclopentadienyl) ruthenium (11) in the form of an orange salt.

¹ H NMR [acetone-d6, Me4Si, δ / ppm (multiplicity, attribution)]: 9.51 [d, Hmeta bipyridine], 8.66 [m, H-aromatic naphthalene + Hortho bipyridine], 8.09 [m, bipyridine], 7.97 [ d, Aromatic naphthalene], 7.77 [d, H-aromatic naphthalene], 7.57 [m, H-aromatic naphthalene], 7.45 [t, H-aromatic phosphate], 7.34, [t, H-aromatic phosphate], 7.16 [m , H-aromatic naphthalene], 5.22 [m, -CH2O- bipyridine + -CH- polylactide main chain], 4.95 [s, r | ^5- cyclopentadienyl], 4.30 [m, CH- polylactide terminal], 1.55 [m, -CH3 polylactide main chain + -CH3 polylactide terminal].

Example 7

Alternative synthesis of an organometallic ruthenium complex containing a heteroaromatic macroligand: (2,2'-bipyridine-4,4'-di-ylbis {methylene} bis (2- {2- (2-hydroxypropanoyloxy) poly (lactic acid) -yl triflate } propanoate) k ² N, N ') (triphenylphosphane) (η ⁵ -αία1ορβηίΗάίθηί1ο) ruthenium (II) Compound 5

The synthesis was carried out using Schlenk techniques under an inert nitrogen atmosphere and the solvents were previously dried and distilled under a nitrogen atmosphere. 70 mg of [RuCp (PPhs) 2CI] were dissolved in anhydrous dichloromethane. Then 450 mg of 2,2'-bipyridine-4,4'-diylbis {methylene} bis (2— {2— (2-hydroxypropanoyloxy) poly (lactic acid) -yl} propanoate) obtained in example 1 were added and 24.6 mg of AgCFsSOs. The obtained mixture was refluxed for 3 h with stirring. It was allowed to stand and the solution was filtered to remove the precipitated AgCl. Then the product was dried in vacuo, washed with hexane and recrystallized with anhydrous dichloromethane / hexane, thus obtaining about 430 mg

43/59 (2,2'-bipyridine-4,4'-di-ylbis {methylene} bis (2 {2- (2-hydroxypropanoyloxy) poly (lactic acid) -yl} propanoate) k ² N triflate, N ') (triphenylphosphane) (r | ^5- cyclopentadienyl) ruthenium (II) in the form of an orange salt.

¹ H NMR [acetone-d6, Me4Si, δ / ppm (multiplicity, assignment)]: 9.53 [d, Hmeta bipyridine], 8.11 [s, Hortho bipyridine], 7.69 [d, Hpaz-a bipyridine], 7.60-7.10 [ m, H-aromatic phosphane], 5.48 [s, CH2O-bipyridine], 5.20 [m, -CH- polylactide main chain], 4.97 [s, r | ^5- cyclopentadienyl], 4.32 [m, -CH polylactide end], 1.57 [m, -CH3 polylactide backbone], 1.40 [m, -CH3 polylactide end].

Example 8

Alternative synthesis of an organometallic ruthenium complex containing a heteroaromatic macroligand: [(1,1 '{1, 1' - (1, 1 '- {2,2'-bipyridine-4,4'-diylbis (methylene) triflate } bis (oxy) bis (l-oxopropane-2,1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-di-yl) di (2S, 3S, 4S, 5R, 6R) -3,4,5,6-tetrahydroxyoxane-2carboxylate) - k ² N, N '] (triphenylphosphane) (η ⁵ -cyclopentadienyl) ruthenium (II) - Compound 6

The synthesis was carried out using Schlenk techniques under an inert nitrogen atmosphere and the solvents were previously dried and distilled under a nitrogen atmosphere. 70 mg of [RuCp (PPhs) 2CI] were dissolved in anhydrous dichloromethane. Then 450 mg of 1.1 '- {1.1' - (1.1 '- {2,2'-bipyridine-4,4'di-ilbis (methylene)} bis (oxy) bis ( 1-oxopropane-2,1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-di-yl) di (2S, 3S, 4S, 5R, 6R ) -3,4,5,6-tetrahydroxyoxane-2carboxylate) and 24.6 mg of AgCFsSOs. The obtained mixture was refluxed for 3 h with stirring. It was allowed to stand and the solution was filtered to remove the precipitated AgCl. The product was then vacuum dried, washed with hexane and

44/59 recrystallized with anhydrous dichloromethane / hexane, thus obtaining 400 mg of [(1,1 '- {1,1' - (1,1 '- {2,2'bipyridine-4,4'- di-ilbis (methylene)} bis (oxy) bis (1-oxopropane2,1-di-yl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (loxopropane-2,1-di- il) di (2S, 3S, 4S, 5R, 6R) -3,4,5,6-tetrahydroxyoxane-2-carboxylate) - k ² N, N '] (triphenylphosphane) (η ⁵ cyclopentadienyl) ruthenium (II) title in the form of an orange salt.

¹ H NMR [acetone-d6, Me4Si, δ / ppm (multiplicity, assignment)]: 9.53 [d, Hmeta bipyridine], 8.10 [s, Ho ^ t ^ o bipyridine], 7.677.11 [m, aromatic H-phosphane + bipyridine], 5.49-5.31 [m, H glucuronic ester], 5.20 [m, -CH2O- bipyridine + -CH- polylactide main chain], 4.96 [s, r | ⁵ -cyclopentadienyl], 4.30 [m, -CH- polylactide terminal + H glucuronic ester], 3.47-3.29 [m, H glucuronic ester], 1.55 [m, -CH3 polylactide main chain], 1.39 [m, -CH3 polylactide terminal].

Example 9

Synthesis of a macromolecular phosphane: 1 - ({1 - ({1- (benzyloxy) l-oxopropane-2-yl} oxy) -1- (poly- (lactic acid))} -1oxopropane-2-yl) -4 - (diphenylphosphine) benzoate

The synthesis was carried out using Schlenk techniques under an inert nitrogen atmosphere and the solvents were previously dried and distilled under a nitrogen atmosphere. A mixture of 1 g of 3,6-dimethyl-1,4-dioxane-2,5-dione, 28.25 mg of dimethylaminopyridine and 11.98 μΐ of isopropanol was heated to 135 ° C in an oil bath and with stirring. Once the 3,6dimethyl-1,4-dioxane-2,5-dione had melted, it took 5 minutes. At the end of this time the reaction was stopped with the addition of an excess of a methanol / water mixture. Then, the product was precipitated in about 50 ml of a methanol / water mixture. The solvent was evaporated in vacuo and the product was

45/59 washed with diethyl ether and vacuum dried. Then 270 mg of this polymer was dissolved in anhydrous THF and 10 μΐ of triethylamine were added. The reaction proceeded for 1 h. At the end of this time 23 mg of 4- (diphenylphosphane) benzoic acid were added and the reaction proceeded at the reflux temperature of the THF until complete removal of the water formed during the reaction using a Dean-Stark assembly. Finally the product was dried in vacuo, thereby obtaining 700 mg of the title compound as a white product.

¹ H NMR [CD3CI3, Me4Si, δ / ppm (multiplicity, assignment)]: 7.41-7.20 [m, benzyl and phosphane H-aromatics], 5.19 [m, -CH main polylactide chain], 4.39 [q, -CH- polylactide terminal], 1.52 [m, -CH3 polylactide main chain], 1.41 [m, -CH3 polylactide terminal].

Example 10

Synthesis of an iron organometallic complex containing a macromolecular phosphane: [1 - ({1 - ({1- (benzyloxy) -1-oxopropane2-yl} oxy) -1- (poly- (lactic acid))} - l- oxopropane-2-yl 4 (diphenylphosphino) benzoate-k ¹ P] (carbonyl) (iodide) (η ⁵ cyclopentadienyl) iron (II) - Compound 7

The synthesis was carried out using Schlenk techniques under an inert nitrogen atmosphere and the solvents were previously dried and distilled under a nitrogen atmosphere. 810 mg of [FeCp (CO) 2l] were dissolved in anhydrous acetone. Then 900 mg of 4- (diphenylphosphane) benzoic acid (BZA) were added. The mixture was irradiated with UV (230V lamp, 300W) for 3 h with stirring. The solution was left to stand and filtered; then the filtrate solvent was evaporated. The obtained compound was washed with hexane and recrystallized with anhydrous dichloromethane / hexane, obtaining the desired compound [FeCp (P (Ph2) (BZA)) (CO) I]. 95 mg of this compound were dissolved in about 50 ml of anhydrous THF and 50

46/59 μΐ of triethylamine. The reaction proceeded for 1 h. At the end of this time 420 mg of the desired polymer was added and the reaction proceeded at the reflux temperature of the THF until complete removal of the water formed during the reaction using a Dean-Stark assembly. Finally the product was dried in vacuo, thus obtaining 390 mg of the compound [1— ({1— ({1 - (benzyloxy) -l-oxopropane-2-yl} oxy) -1- (poly- (lactic acid) ))} 1-oxopropane-2-yl 4- (diphenylphosphino) benzoate-k ¹ ?] (carbonyl) (iodide) (r | ^5- cyclopentadienyl) iron (II) of the title as a neutral colored solid compound brownish green.

¹ H NMR [dmso-d6, Me4Si, δ / ppm (multiplicity, attribution)]: 7.90-7.30 [m, H aromatics phosphane + H aromatics benzyl], 5.1 [m, r | ^5- cyclopentadienyl + -CH- polylactide main chain + -CH2O benzyl], 4.63 [q, -CH- polylactide terminal], 1.24 [m, -CH3 polylactide main chain], 1.24 [m, -CH3 polylactide terminal] ].

The monomodal character of the macromolecule distribution, shown in Figures 2a to 2f, shows a dispersivity of 1.1 for compound 6, 1.2 for compounds 2, 3 and 5, 1.3 for compound 4 and 1.4 for compound 1, which shows the presence of a single population / species of compound (monomodal character) with very similar molecular mass values (dispersivity close to 1).

Example 11

Synthesis of a macromolecular phosphane: tris (1- (1- (1-hydroxypropanoyloxy) poly (lactic acid) ylpropanoate) phosphane

The synthesis was carried out using Schlenk techniques under an inert nitrogen atmosphere and the solvents were previously dried and distilled under a nitrogen atmosphere. A mixture of 1 g of (3S) -cis-3,6-dimethyl-1,4-dioxane-2,5-dione, 56.5 mg of

47/59 dimethylaminopyridine and 30 mg of tris (hydroxymethyl) phosphine was heated to 120 ° C in an oil bath under stirring. After (3S) -cis-3,6-dimethyl-1,4-dioxane-2,5-dione was melted for 15 minutes, at the end of this time the reaction was stopped with the addition of an excess of a mixture of methanol / water. Then, the product was precipitated in about 50 ml of a methanol / water mixture. The solvent was evaporated in vacuo and the product obtained was washed with diethyl ether and dried in vacuo, thus obtaining about 900 mg of the title compound as a white product.

¹ H NMR [CDCI3, Me4Si, δ / ppm (multiplicity, attribution)]: 5.16 [m, -CH- polylactide main chain], 4.58 [s, -CH2O phosphine], 4.36 [q, -CH- polylactide terminal ], 1.58 [m, CH3 polylactide backbone], 1.50 [m, -CH3 polylactide end].

Example 12

Synthesis of an iron organometallic complex containing a macromolecular phosphane: [tris (l- {1- (1hydroxypropanoyloxy) poly (lactic acid) yl} propanoate) phosphane-k ¹ P] (carbonyl) (iodide) (η ⁵ cyclopentadienyl) iron (II) - Compound 8

The synthesis was carried out using Schlenk techniques under an inert nitrogen atmosphere and the solvents were previously dried and distilled under a nitrogen atmosphere. 40 mg of [FeCp (CO) 2I] was dissolved in anhydrous acetone. Then 445 mg of tris (1- {1- (1-hydroxypropanoyloxy) poly (lactic acid) -yl} propanoate) phosphate prepared in example 11 were added. The mixture obtained was irradiated with UV (230V lamp, 300W ) for 8 hours under stirring and nitrogen atmosphere. The solution was left to stand and filtered; then the filtrate solvent was evaporated. The obtained compound was washed with hexane and recrystallized with anhydrous acetone / n-hexane, obtaining

48/59 thus about 450 mg of the title compound as a neutral brownish green solid.

¹ H NMR [CDCI3, Me4Si, δ / ppm (multiplicity, attribution)]: 5.16 [m, -CH2O- phosphine, -CH- polylactide backbone], 4.63 [s, r | ^5- cyclopentadienyl], 4.31 [m, -CH- polylactide terminal], 1.57 [m, -CH3 polylactide main chain], 1.50 [m, -CH3 polylactide terminal]

Example 13

Alternative synthesis of an organometallic ruthenium complex containing a macromolecular phosphane of formula (III): [(1 - ({1 - ({1- (benzyloxy) -l-oxopropane-2-yl} oxy) -1- ( poly (lactic acid)} -l-oxopropane-2-yl) -4 (diphenylphosphino) benzoate-k ^{* 1} P] ((2-benzoylopyridine) -k ² N, O) (η ⁵ cyclopentadienyl) ruthenium (II) - Compound 9

137 mg ({1 - ({1- (benzyloxy) -l-oxopropane-2-yl} oxy) -1 (poly- (lactic acid))} - 1-oxopropane-2-yl) were dissolved in about 50 ml of anhydrous THF and 50 μΐ of triethylamine were added. The reaction proceeded for 1h. After this time 68 mg of [(2-benzoylopyridine) -k ² N, 0] [(4- (diphenylphosphinobenzoate)) -k ¹ ?] (Η5cyclopentadienyl) ruthenium (II) triflate were added and the reaction proceeded at a temperature of reflux of the THF until complete removal of water formed during the reaction using a Dean-Stark assembly. The product was dried in vacuo, thereby obtaining 93 mg of the title compound as a violet solid product.

¹ H NMR [acetone-d6, Me4Si, δ / ppm (multiplicity, attribution)]: 9.89 [d, Hortho pyridine], 8.30 [d, H _and ta pyridine], 8.05 [t, Hpa ^ a pyridine], 7.95 [ d, H-aromatic phosphate], 7.60-7.20 [m, Haromatic phosphate + H-aromatic benzyl], 5.20 [m, -CH2-benzyl of the polylactide end group, -CH- polylactide backbone], 4.88 [s, r | ^5- cyclopentadienyl], 4.32 [m, polylactide terminal -CH49 / 59],

1.55 [m,

-CH3 polylactide main chain], 1.47 [m, -CH3 polylactide terminal]

II - Biological activity

Example 14

In vitro cell viability inhibition assays

As an example, the cytotoxic activity of compounds 1, 2, 3, 4, 5 and 6 was studied, by determining the concentration required for the 50% inhibition of cell viability (IC50), a parameter used to evaluate the inhibition of activity in vitro, in human tumor lines for some compounds of the present invention.

a) The cytotoxic activity of compounds 5 and 6 was assessed in human tumor cells of MCF-7 breast adenocarcinoma proceeding as follows for each test compound:

The culture of the human breast carcinoma cell line (MCF-7; ATCC) was carried out in DMEM medium (Gibco) containing GlutaMax I and was completed with 10% FBS and 1% penicillin-streptomycin and maintained at 37 ° C in an atmosphere humidified containing 5% CO2.

Cell culture was carried out in flasks containing the medium proper to cell proliferation and which allows cell adhesion.

When the cells reached the necessary confluence, they were dissociated by adding a 0.05% trypsin EDTA solution (Gbico). Cell viability was assessed by the MTT assay which measures the reduction of 3- (4,5dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) to formazan blue by viable cells. For this, the cells were seeded in 200 μΐ of complete cell medium in 96-well plates. Cell density was 2 χ 10 ⁴ cells (MCF-7) viable per well.

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The cells were adhered for 24 h, followed by the addition of the various dilutions in medium (200 μΐ) of the test compound. The test compound was first solubilized in DMSO and then in the cell medium and added to the cells in concentrations 1-100 μΜ. The final concentrations of DMSO in the medium were less than 0.5%. After 24 h and 72 h of incubation, 37 ° C / 5% CO2, the medium was replaced by 200 μΐ of the MTT solution (0.5 mg / ml in phosphate-PBS buffer). After 3-4 h of incubation, the MTT solution was removed and the formazan crystals formed by the viable cells were dissolved in DMSO (200 μΐ). Cell viability was assessed by measuring absorbance at 570 nm, using the plate spectrophotometer. The cytotoxicity of the test compound was quantified by calculating the concentration of drug that inhibits the growth of 50% of the cells (IC50) (GraphPad Prism software). The evaluation was carried out with at least two independent experiments, each comprising six replicates per concentration. The cell-viability dose-response curves, respectively after 24 h and 72 h of incubation, are represented in the graphs of Figures 3a and 3b. The results obtained clearly show that both compounds 5 and 6 are cytotoxic to the MCF-7 cell line in the do-s-micromolar range. In addition, there is a clear dose-response relationship.

b) The cytotoxic activity of compounds 5 and 6 was evaluated in human A2780 ovarian carcinoma cells and in human breast carcinoma cells MDA-MB-231, proceeding as follows for each test compound:

Cultures of human breast carcinoma cell lines (MDA-MB-231; ATCC) and ovary (A2780, ATCC), were performed in DMEM (Gibco) medium containing GlutaMax I (MDA-MB231) or RPMI (A2780) and they were supplemented with 10% FBS and 1% penicillin-streptomycin and maintained at 37 ° C in a humidified atmosphere containing 5% CO2.

51/59

Cell culture was carried out in flasks containing the medium proper to cell proliferation and which allows cell adhesion.

When the cells reached the necessary confluence, they were dissociated by adding a 0.05% trypsin EDTA solution (Gbico). Cell viability was assessed by the MTT assay which measures the reduction of 3- (4,5dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) to formazan blue by viable cells. For this, the cells were seeded in 200 μΐ of complete cell medium in 96-well plates. Cell density was 2 χ 10 ⁴ cells (MDA-MB-231 and A2780) viable per well. The cells were adhered for 24 h, followed by the addition of the various dilutions in medium (200 μΐ) of the test compound. The test compound was first solubilized in DMSO and then in the cell medium and added to the cells in concentrations 1-100 μΜ. The final concentrations of DMSO in the medium were less than 0.5%. After 24 h and 72 h of incubation, 37 ° C / 5% CO2, the medium was replaced with 200 μΐ of the MTT solution (0.5 mg / ml in phosphate-PBS buffer). After 3-4 h of incubation, the MTT solution was removed and the formazan crystals formed by the viable cells were dissolved in DMSO (200 μΐ). Cell viability was assessed by measuring absorbance at 570 nm, using the plate spectrophotometer. The cytotoxicity of the test compound was quantified by calculating the concentration of drug that inhibits the growth of 50% of the cells (IC50) (GraphPad Prism software). The evaluation was carried out with at least two independent experiments, each comprising six replicates per concentration. The cell-viability dose-response curves after 72 h of incubation are shown in the graphs of Figures 4a and 4b. The results obtained show that both compounds 5 and 6 are cytotoxic to

52/59 the cell lines MDA-MB-231 and A2780 in the micromolar range. In addition, there is a clear dose-response relationship.

c) The cytotoxic activity of compounds 1, 2, 3 and 4 was evaluated in tumor cells of human tumor lines of the A2780 ovary, MCF-7 breast, U87 glioma and A345 melanoma, proceeding as follows for each test compound:

Cultures of human breast carcinoma cell lines (MCF-7; ATCC), ovary (A2780, ATCC), glioma (U87, ATCC) and melanoma (A345; ATCC) were performed in DMEM medium (Gibco) containing GlutaMax I (MCF-7; U87; A345) or RPMI (A2780) and were supplemented with 10% FBS and 1% penicillin-streptomycin and maintained at 37 ° C in a humidified atmosphere containing 5% CO2. Cell culture was carried out in flasks containing the medium proper to cell proliferation and which allows cell adhesion. When the cells reached the necessary confluence, they were dissociated by adding a 0.05% trypsin-EDTA (Gbico) solution. Cell viability was assessed by the MTT assay that measures the reduction of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) to formazan blue by viable cells. For this, the cells were seeded in 200 μΐ of complete cell medium in 96-well plates. Cell density was 2 χ 104 (MCF-7) viable cells per well. The cells were adhered for 24 h, followed by the addition of the various dilutions in medium (200 μΐ) of the test compound. The test compound was first solubilized in DMSO and then in the cell medium and added to the cells in concentrations 1-100 μΜ. The final concentrations of DMSO in the medium were less than 0.5%. After 24 h and 72 h of incubation, 37 ° C / 5% CO2, the medium was replaced with 200 μΐ of the MTT solution (0.5 mg / ml in phosphate buffer - PBS). After 3-4 h of incubation, the MTT solution was removed and the formazan crystals formed by the viable cells were dissolved in DMSO (200 μΐ). Cell viability was assessed by measuring the

53/59 absorbance at 570 nm, using the plate spectrophotometer. The cytotoxicity of the test compound was quantified by calculating the concentration of drug that inhibits the growth of 50% of the cells (IC50) (GraphPad Prism software). The evaluation was carried out with at least two independent experiments, each comprising six replicates per concentration. The results obtained after 48 h of incubation are presented in the graphs of Figures 5a to 5d, respectively, demonstrating that all compounds are cytotoxic for the four cell lines. Compounds 3 and 4 (containing the triphenylphosphane ligand), are the most active (in relation to compounds 1 and 2 which contain a 00 ligand). Note the remarkable values obtained for the highly deadly glioma line (the value found in the literature for cisplatin is 130 ± 53 μΜ (0. Patapova, A. Haghighi, F. Bost, C. Liu, MJ Birrer, R. Gjerset, D. Mercota, J. Biol. Chem. 1997, 272: 14041-14044).

As shown in Figures 1 to 1, the relative change (%) of the absorbance at fixed wavelength over time (> 24 h) respectively for compounds 1, 2, 3, 4, 5 and 6 in a mixture of 5% DMSO: 95% of cell medium shows adequate chemical stability in aqueous medium of the compounds.

The results are among the lowest cytotoxicity values for compounds with piano-like structure (eg PCA Bruíjnincx, PJ Sadler, In: in R. Van Eldik, CD Hubbard (Eds), Advances in Inorganic Chemistry, 61, Academic Press, London, 2009, pp. 1-61) and exhibit activity over a range of micromolar concentrations, in most cases being better than that of the cisplatin reference compound as shown in Table 1 below. Table 1 shows the IC 50 values, the concentration required for inhibiting cell viability by 50% in MCF7, A2780 and MDA-MB-231 cells, corresponding to two new compounds,

54/59 compounds 5 and 6, whose cell viability dose-response curves are shown in Figures 3b), 4a) and 4b).

TABLE 1

IC50 after 72h of incubation MCF-7 (μΜ) A2780 (μΜ) MDA-MB- 231 (μΜ) Compound 5 4.09 ± 1.97 3.4 ± 1.3 2.7 ± 0.55 Compound 6 4.62 ± 1.15 2.20 ± 0.85 5.96 ± 3.25 Cisplatin 28 ± 6.0 2.0 ± 0.10 39 ± 5.0

Table 2 below shows the IC50 values in MCF-7 cells, corresponding to compounds 5 and 6, whose dose-response curves for cell viability are shown in Figure 3a).

TABLE 2

IC50 after 24h incubation MCF-7 (μΜ) Compound 5 4.25 ± 1.15 Compound 6 5.00 ± 1.65

Once the tumor tissue is reached and due to the effect of improved permeability and retention (RPE), the compounds can accumulate there, increasing the efficiency of the drug and thus allowing to reduce the number of treatment doses 55/59 and the time spacing, which represents a major advantage in chemotherapy.

Studies of cell distribution of these compounds in tumor cells show that they are mostly located in the cytoskeleton, nucleus and / or cytoplasm of these cells, indicating that they accumulate inside the cell, which opens up good prospects for their use in targeted therapy, namely to intracellular targets. The graph of Figure 6 shows the cell distribution of compounds 5 and 6 in human breast tumor cells MCF-7 after 24 h of incubation, with the observed differences related to the molecule of biological interest (-OH in compound 5 vs. sugar) in compound 6) used in each of the different compounds.

It can be concluded from the evidence that drugs according to the present invention that include molecules recognized by the tumor target reach tumor cells with high precision. The efficiency of these drugs is also enhanced by the fact that the remaining product from the biodegradation of the polymer, which contains the organometallic unit, also presents cytotoxicity to tumor cells. This characteristic of the compounds of the present invention may also be the key to overcoming the terrible side effects of chemotherapy, caused by the drugs currently in use.

The ability to act at the level of metastases is extremely important, since the vast majority of deaths caused by cancer are due to metastases and not to the primary tumor. The compounds according to the present invention are also expected to have favorable properties in combating metastases, in addition to acting on the primary tumor, taking into account, first of all, the excellent results obtained in vitro on highly metastatic cell lines, like the MDA-MB-231 and secondly,

56/59 the results of in vivo studies in nude mice using low molecular weight compounds (ie that do not include polymers in their structure) by us already synthesized. The results obtained in nude N: NIH (S) II-nu / nu mice, who were induced a tumor (MDA-MB-231) in the mammary gland, showed that the injection of 2.5 mg / kg per day of the study drug , for 10 days, induces tumor suppression by about 50% compared to control mice. The most important result is the absence of metastases in the main organs (lung, kidneys, liver, heart) after treatment, while all control mice showed metastases. These results suggest that this drug can act not only on the primary tumor, but also by inhibiting metastatic behavior, probably interfering with tumor angiogenesis.

In addition, the compounds of the present invention cause cell death by apoptosis, which is a controlled cell death mechanism that prevents lysis of the affected cell into the surrounding environment, apparently by mitochondrial route, as evidenced by apoptosis and electron microscopy assays. sweep as described below.

Example 15

Apoptosis assays

An apoptotic process detection kit, the Human Apoptosis Array, was used, which provides a fast and sensitive method to simultaneously detect the relative expression levels of 35 proteins related to the apoptosis process (control cells indicate a level of expression 100%) to test apoptosis induced by compounds 5 and 6 in human breast cancer cells MCF-7, comparing with

57/59 untreated cells, proceeding according to the manufacturer's instructions.

After a 24 h incubation with compounds 5 and 6, there was a decrease in the expression of the catalase and SMAC diablo proteins under study, suggesting that the apoptosis process is induced through the intrinsic-mitochondrial pathway. The intrinsic pathway is activated by intracellular or extracellular stress. The signals that are transduced in response to these stimuli converge mainly to the mitochondria. This organelle integrates cell death stimuli, inducing mitochondrial permeabilization and the consequent release of pro-apoptotic molecules present in it. These results also suggest that the complexes appear to induce high levels of oxidative stress in tumor cells. The results obtained are shown in the graph in Figure 7.

Example 16

Determination of the cell death mechanism caused by compounds 5 and 6 type of cell death mechanism induced by compounds 5 and 6 in MCF-7 tumor cells after 48 h of incubation at a concentration of 10 μΜ was determined using the annex V cytometry assay / Propidium lodide (PI). This assay is commonly used to determine viable, apoptotic or necrotic cells according to differences in the integrity and permeability of the plasma membrane. In general, the Annexin V / PI assay is used to study the mechanism of cell death (Rieger et al. 2011). The results showed that the incubation of compounds 5 and 6 led to an increase in the percentage of cells stained with Annexin V (Figure 8) compared to the control cells. Annexin V is a marker of early apoptosis. This indicates that in the present case the compounds cause apoptosis. There is also a

58/59 increase in double stained cells also suggesting the presence of late apoptosis. Cisplatin was used as a positive control, since it is known to induce apoptosis.

Example 17

Effect of compounds 5 and 6 on the cytoskeleton

According to previous results that suggested that both compounds 5 and 6 interact with the cytoskeleton (Figure 9), an assay based on an immunofluorescence technique was performed using the MCF-7 tumor cells. In this immunofluorescence assay, the Alexa Fluor 488® phalloidin, which is a filamentous actin probe (F-actin) with high affinity conjugated to the Alexa Fluor® 488 fluorescent green dye, was used. As shown in Figure 9, in order to to obtain a staining of the nucleus, DAPI (blue) was used, and it can be seen that the control cells maintain the integrity of the F-actin filaments as well as a clear delimitation of the cells. In contrast, cells incubated with compounds 5 and 6 have a cytoskeleton that has lost its organization. In addition, there may also be the appearance of dot-shaped structures within the nucleus of cells treated with both compounds.

Claims (7)

1. Macromolecular complexes of transition metals characterized by being: (2,2'-bipyridine-4,4'-diylbis {methylene} bis (2— {2— (2-hydroxypropanoyloxy) poly (lactic acid) -ylJpropanoate) -k ² N, Ν ') hexafluorophosphate (η ⁵ cyclopentadienyl) ruthenium (II); [(1, 1 '- {1,1' - (1,1 '- {2,2'-bipyridine4,4'-di-ylbis (methylene)} bis (oxy) bis (1-oxopropane-2 hexafluorophosphate , 1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-di-yl) dianthracene-9-carboxylate) -k ² N, Ν '] (carbonyl ) (η ⁵ cyclopentadienyl) ruthenium (II); [(1,1 '- {1,1' - (1,1 '- {2,2'-bipyridine-4,4'-diylbis (methylene)} bis (oxy) bis (l-oxopropane-2) triflate , 1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-diyl) dianthracene-9-carboxylate) k ² N, N '] (triphenylphosphane) (r | ^5- cyclopentadienyl) ruthenium (11); [(1,1 '- {1,1' - (1,1 '- {2,2'-bipyridine-4,4'-diylbis (methylene)} bis (oxy) bis (l-oxopropane-2) triflate , 1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-diyl) dinaphthalene-2-carboxylate) k ² N, N '] (triphenylphosphane) (r | ^5- cyclopentadienyl) ruthenium (11); (2,2'-bipyridine-4,4'-diylbis {methylene} bis (2— {2— (2-hydroxypropanoyloxy) poly (lactic acid) -ylJpropanoate) -k ² N, Ν ') (triphenylphosphane) triflate (η ⁵ cyclopentadienyl) ruthenium (II); [(1,1 '- {1,1' - (1,1 '- {2,2'-bipyridine-4,4'-diylbis (methylene)} bis (oxy) bis (l-oxopropane-2) triflate , 1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-di-yl) di (2S, 3S, 4S, 5R, 6R) -3.4 , 5,6-tetrahydroxyoxane-2carboxylate) -k ² N, Ν '] (triphenylphosphane) (η ⁵ cyclopentadienyl) ruthenium (II); [1- ({1 - ({1- (benzyloxy) -l-oxopropane-2-yl} oxy) -1- (poly (lactic acid))} - 1-oxopropane-2-yl 4 (diphenylphosphino) benzoate- k ^{1 '} ] (carbonyl) (iodide) (η ^{3 * 5} cyclopentadienyl) iron (II); [tris (1— {1— (1-hydroxypropanoyloxy) poly (lactic acid) ylpropanoate) phosphane-k ¹ ?] (carbonyl) (iodide) (η ⁵ cyclopentadienyl) iron (II); or [(1 - ({1 - ({1- (benzyloxy) -l-oxopropane-2yl} oxy) -1- (poly- (lactic acid)} -l-oxopropane-2-yl) -4 ( diphenylphosphino) benzoate-klP] ((2-benzoylopyridine) k2N, O) (p5-cyclopentadienyl) ruthenium (II) and their pharmacologically acceptable salts. 2. Bidentate macroligands characterized by being: l, l '- {l, l' - (l, l '- {2,2'-bipyridine-4,4'-diylbis (methylene)} bis (oxy) bis (1-oxopropane-2,1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-diyl) dianthracene-9-carboxylate; l, l '- {l, l' - (l, l '- {2,2'-bipyridine-4,4'-diylbis (methylene)} bis (oxy) bis (l-oxopropane-2,1-diyl )) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-diyl) dinaphthalene-2-carboxylate; or l, l '- {l, l' - (l, l '- {2,2'-bipyridine-4,4'-diylbis (methylene)} bis (oxy) bis (l-oxopropane-2,1- di-il)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane- 2,1-di-yl) di (2S, 3S, 4S, 5R, 6R) -3,4,5,6-tetrahydroxyoxane-2carboxylate. Pharmaceutical composition characterized in that it comprises a pharmaceutically effective amount of at least one macromolecular transition metal organometallic complex according to claim 1. Pharmaceutical composition according to claim 3, characterized in that it comprises a pharmaceutically effective amount of at least one macromolecular transition metal organometallic complex according to claim 1, in association with other active ingredients and / or with vehicles and / or pharmaceutically acceptable excipients. Pharmaceutical composition according to claim 4, characterized in that it is for use in the therapy and / or prevention of cancer, as an antitumor agent in solid, liquid and / or metastatic tumors and / or as a radiosensitizing agent. 6. The transition metal macromolecular organometallic complex according to claim 1, for use in cancer therapy and / or prevention, as an antitumor agent in solid, liquid and / or metastatic tumors and / or as a radiosensitizing agent, characterized in that said compound be: (2,2'-bipyridine-4,4'-diylbis {methylene} bis (2— {2— (2-hydroxypropanoyloxy) poly (lactic acid) -ylJpropanoate) -k ² N, Ν ') hexafluorophosphate (η ⁵ cyclopentadienyl) ruthenium (II); [(1, 1 '- {1, 1' - (1,1 '- {2,2'-bipyridine4,4'-di-ylbis (methylene)} bis (oxy) bis (l-oxopropane-2 hexafluorophosphate , 1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-di-yl) dianthracene-9-carboxylate) -k ² N, Ν '] (carbonyl ) (η ⁵ cyclopentadienyl) ruthenium (II); [(1,1 '- {1,1' - (1,1 '- {2,2'-bipyridine-4,4'-diylbis (methylene)} bis (oxy) bis (l-oxopropane-2) triflate , 1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-diyl) dianthracene-9-carboxylate) k ² N, N '] (triphenylphosphane) (r | ^5- cyclopentadienyl) ruthenium (11); [(1, 1 '- {1,1' - (1,1 '- {2,2'-bipyridine-4,4'-diylbis (methylene)} bis (oxy) bis (l-oxopropane-2) triflate , 1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane2,1-diyl) dinaphthalene-2-carboxylate) k ² N, N '] (triphenylphosphane) (r | ^5- cyclopentadienyl) ruthenium (11); (2,2'-bipyridine-4,4'-diylbis {methylene} bis (2— {2— (2-hydroxypropanoyloxy) poly (lactic acid) -ylJpropanoate) -k ² N, Ν ') (triphenylphosphane) triflate (η ⁵ cyclopentadienyl) ruthenium (II); [(1, 1 '- {1, 1' - (1, 1 '- {2,2'-bipyridine-4,4'-diylbis (methylene)} bis (oxy) bis (l-oxopropane-2) triflate , 1-diyl)) bis (poly (lactic acid) -yl))} bis (oxy) bis (1-oxopropane- 2,1-di-yl) di (2S, 3S, 4S, 5R, 6R) -3,4,5,6-tetrahydroxyoxane-2carboxylate) -k ² N, Ν '] (triphenylphosphane) (η ⁵ cyclopentadienyl) ruthenium (II); [1- ({1 - ({1- (benzyloxy) -l-oxopropane-2-yl} oxy) -1- (poly (lactic acid))} - 1-oxopropane-2-yl 4 (diphenylphosphino) benzoate- k ^{1 '} ] (carbonyl) (iodide) (η ⁵ cyclopentadienyl) iron (II); [tris (1— {1— (1-hydroxypropanoyloxy) poly (lactic acid) ylpropanoate) phosphane-k ¹ ?] (carbonyl) (iodide) (η ⁵ cyclopentadienyl) iron (II); or [(1 - ({1 - ({1- (benzyloxy) -l-oxopropane-2yl} oxy) -1- (poly- (lactic acid)} -l-oxopropane-2-yl) -4 ( diphenylphosphino) benzoate-klP] ((2-benzoylopyridine) k2N, O) (g5-cyclopentadienyl) ruthenium (II); and their pharmacologically acceptable salts. Pharmaceutical composition according to any one of claims 3 to 5, or transition metal macromolecular organometallic complex for use in cancer therapy and / or prevention, as an antitumor agent in solid, liquid and / or metastatic tumors and / or as radiosensitizing agent according to claim 6, characterized in that said composition or said transition metal macromolecular organometallic complex is to be administered topically, intravenously, subcutaneously or intraperitoneally.